6-alkyldiosgenins, and degradation to diosones



United States Patent G-ALKYLDIOSGENINS, AND DEGRADATION T DIGSONES Bjarte Liiken, Roosevelt, and Hector Flores, San Juan; Puerto Rico, assignors to G. D. Searle & Co., Chicago, 11]., a corporation of Delaware 1N0 Drawing. ApplicationMayne-1958 I Serial N0..7.38,007

4f'ClaimS. (CL 260-23955) The present invention :relates to ta-noyel methodior "the preparation :of a group :of steroidal intermediates; iIn partieularit-relates tot'a process of degrading .6zalkylpated ,sapogenins to .6avalkylw16f3 (5-acetoxy-sy methyl- 1pentanoyl0Xy)-4-pregnene-3,20dione and therefrom to 6a-alkyl-4,16:pregnadiene:3,20-diones. .T he latter, which 1316Ih6 :subjectpmatter of;a separate application, can bel which .are ihighlyactive :progestational agents. .A typical :method for the :CQIlVfilfSiOD of the .,6u-alky1-4,'16;pregnatdiener32j0=diones to progestationally active compounds 1 is given inone'of the examples.

fliheproeesses of this invention follow thetgeneralzr. ,ac- "tion sequence illustrated in .the following itabledn'whi Rvcan nrepresent hydrogen or a lower -,al kyl::radica1. 1

.iFrom .diosgenin there 1 is :prepared 6fl-alkyl22risoailo- :spirostane-StiM-diol (I), ,a compoundpf a-type which. is :also disclosed in a copending application byMiramontes, zkomero and -Ahuad, Serial No. 68,6;562,.fi1ed September 27, 195-7. ,zThisldiol (1-).istnextoxidizedtto-the5ahY droxy-6fiialkyl 22Tisoallospirostan-B-one (II). Ereatment :r eificiency of the over-all reaction. The/resulting -3,26=didro1yzed'withstrong alkali (e. g g. causticqsoda orpotash) in -a lower. alkanol, suitably methanol, to .saponifyboth the enolic acetate gronpand thel26-acetoxy;group-so as :10 form the '6ocralky1-26 hydroxy-4;20(.22)furostadien-3 tone (EV). Thecornpound Vis reacetylated withyacetic ,anhydride in vatstrong organic base (typically in pyridine or an alkylated pyridine such as lutidine, :picoline :iand .collidine, or in aniline), to yield a 26-,acetate (VI), which 16 .-.p- '(6 acetoxy- 'y emethylpentanoyloxy) r 4 -'1pregnene-3,20-dione (VII). This ester is then sapoliifieclzand dehydrated with alkali to yield the 6a-alkyl-4,16-pregnadiene-3 ,ZO-dione. i

While the .6e-alkyl derivatives tareiof particular interest, the wprocessuis likewise applicable. forthe preparation of the unsubstituted 4,16-pregnadien-3,2O7dione in which R is hydrogen, and which is useful as startingmaterial .for such; compounds as .17,2l dihydroxyprogesterone 1 ice A well-known procedure for the degradation of diosgenin and other sapogenins Marker, -'J. A. C. S. 1940, p. 2526), describes the chromic acid oxidation of the compound of the type IV to the type VII. This procedure gives very low yields in the case so'ftthe compounds in which R is hydrogen and fails practically completely with the 6-alkyl derivatives.

Applicants have now found that the undesirable side reactions which occur in tthe direct oxidation of compounds of the type IV to those of-type VII can be avoided, and 40 to 45% yields by weight,ecan be achieved in the conversions-of th-e compounds of the type III all the way to the compounds of the type of VIII by the intermediate preparation of the compounds ro'fsthe type V and VI. The high yields are obtained because theicomplete isolation of the compounds of the type IV, V, VI, and VII is unnecessary under the experimental conditions employed in the new process described herein. It -is aqspecial advantage of this reaction sequence that costly purification procedures, such as recrystallizations'ortchrornotography, are not required.

The invention will be described in further detail in the following examples, but these are not to be construed as limiting the invention in spirit orin scope. It will be apparent to those skilled in the :art that numerous modifications in mtaerials and methods can be adopted without departing'from'the scope of theiinyention. In the exam ples quantities are indicated as parts bynreight.

CH 1 CH;

VII

Example I A solution of 100 parts of diosgenin in 1340 parts of dichloromethane is treated under ice cooling with a solution containing 160 parts acetone, 270 parts of dichloromethane, 2 parts of sodium acetate, and 70 parts of commercial peroxyacetic acid. The mixture is then maintained at room temperature for 5 hours and at the end of that time washed with 1000 parts of a 5% ferrous sulfate solution to reduce the excess peroxyacetic acid. The organic layer is separated and washed with water, and the washings are reextracted with dichloromethane. The organic extracts are combined and concentrated to dryness on a steam bath, and then 800 parts of heptane are added, and a small head fraction is distilled oil in order to remove residual dichloromethane. The mixture is cooled to 30 C. under agitation, and the crystalline material is collected on a filter. This crystalline material consists predominantly of 5a,6a-epoxy-22-isoallospirostan-Sfi-ol. The mother liquor is evaporated to a small volume, and a second crop is harvested, which is also a mixture of 2 epimeric epoxides containing mainly the B-epoxide. The first crop is dissolved in dichloromethane and then treated with 1300 parts of heptane, and the mixture isdistilledto remove the dichloromethane. Upon complete removal of the dichloromethane, almost pure 5m,6a-epoxy-22-isoallospirostan-35-01 is obtained, melting at about 225-227 C. A solution of 150 parts of this epoxide in 2700 parts of toluene is slowly added to 1500 parts of a 3-molar commercial solution of methylmagnesium bromide. The mixture is then refluxed for 150 minutes, chilled, and treated with water until no more reaction can be observed. It is then subjected to steam distillation,'and the residual suspension is cooled and treated with a mixture of 480 parts of concentrated hydrochloric acid and 400 parts of water. The crude product is collected on a filter, washed and dried. It is Example 2 To an. agitated suspension of 55.5 parts of Gfl-methyl- 22-isoallospiro'stane-3fl,Sa-dioI in 880 parts of acetone,

which is cooled to 15 C., is added in small portions in the course of 45 minutes a solution of 14.8 parts of chromium trioxide in 27 parts of water containing 5 parts of sulfuricacid, the temperature being allowed to'rise to 25 C. Agitation is then continued for minutes,

5 after which 2300 parts of: ice water are added and the esulting" precipitate is collected on a filter, wastage/"int much water, and then with a" 1% aqueous sod bicarbonate sb1ution, and finally, again" with water. The 5ci hydroxy 6a methyl-22 isoallospirostan 3 one thus prepared is sufliciently pure for use in the proce ure of the next two examples. on recrystallization from equal parts of dichloromethane and acetone, a melting point of 244.5-246 C. is obtained. Therotatiori" tub in chloroform is --75.

Example 3 A suspension of 43 parts of 5a -hydroxy-6fl iriethyl-22- isoallospirostan-3-one in 98 parts of acetic anhydride is heated in a sealed tube at 195 C. for 6 hours, after which the contents are cooled, and 40 parts of pyridine are added. The solution is precipitated in a large volume of ice water under agitation, and the resulting mixture is agitated for 3 hours. The aqueous phase is then removed, and the oily residue is repeatedly extracted with water. The residue consists predominantly of 6- methyl-3,26-diacetoxy-3,5,20(22)-furostatriene.

To the crude 6-methyl-3,26-diacetoxy-3,5,20(22)- furostatriene thus obtained is added a solution of parts of potassium hydroxide in 30 parts of water and 150 parts of methanol. This mixture is heated for 45 min utes under reflux with efiicient agitation. The resulting 6a-methyl-26-hydroxy-4,20(22)-furostadien3-one is precipitated by pouring the reaction product resulting from the saponification into 1000 parts of ice water with agita tion. The mixture is then permitted to settle and the aqueous phase is decanted. The oily residue is washed repeatedly with water at 50 C. Prior to each decanta tion it is found advisable to cool the mixture by the addition of ice. The final residue, which has an almost solid consistency, is spread on a ceramic dish for air drying. The dried material is then transferred into a reaction vessel, the ceramic dish is extracted with 45 parts of pyridine, and the extracts are added to the reaction vessel. Finally 44 parts of acetic anhydride are added, and the mixture is maintained at 60 C. for 45 minutes. The 60: methyl 26 acetoxy 4,20(22) furostadien- 3-one thus obtained is precipitated by addition to 1000 parts of ice water. After settling, the aqueous phase is decanted, and the residue is once more washed with water.

The residue is then transferred with 240 parts of dichloromethane into a reaction vessel to which are added 190 parts of glacial acetic acid. Ten parts of water are added to remove any residue of acetic anhydride. The solution thus obtained is cooled to 5 C. and treated by slow addition with a solution of 18 parts of chromium trioxide in 25 parts of water and 20 parts of acetic acid while the mixture is efficiently stirred. In the course of the addition, which takes about 45 minutes, the temperature is permitted to rise'to about 12 C. Agitation is continued for 3 hours at a temperature of about 20 to 25 C. after which Water is added. Further addition of a saturated solution of sodium chloride permits a convenient separation. The aqueous layer is separated and reextracted with dichloromethane, and the combined organic extracts, which are usually green but occasionally bluish-violet in color, are taken to dryness on a steambath. Water is twice added to the residue and distilled off in vacuum to remove residual solvents.

To the 604 methyl 16B (B-acetoxy 'y methylpentanoyloxy) 4 pregnene 3,20 dione thus obtained there are added 190 parts of acetone, and heat is applied until complete solution results. A solution of 15 parts of sodium hydroxide in 240 parts of water is then added, and the mixture is maintained at 45-50 C. for 15 minutes. The reaction mixture is cooled to 0 C. and the resulting precipitate is collected on a filter and washed with a 13:7 mixture of acetone and water. A mixture of 28 parts of the crude product in 280 parts ofacetone is stirred at 25 C. The chromium salts are removed by filtrationthrough a bed of filter aid andthe filtrate is talt'eiiti)" dryness on a steambath. The residues taken up iiimethanol; and chills. to" yield crystals of 6amartyr- 4,repre aaaieae-sioeai ae; melting. at about -180 C. The rotation of a" chloroform solution ca is 152; I

In a mixture-of 2 13 parts of potassium hydroxide, 5 parts of water, and 320 parts of methanol;-=ther'e aresuspended ZOpa-rts ofi 5 orliydroxy'=6B rnethyl 2-2 -i'soallospirostah-B-on; and the mixture is refluxed for '1-0 min ut'es, Then SOO-par tsof water are addedandthqm'ixture isecooled, and-a solid materialiscollec'ted ona-filter and washed with water to neutrality to yield 6a-methyl-22-iso- 4-spirosten-3-one which, recrystallized from methanol, melts at about 2ll 2l3 C. The rotation. of u in chloroform is -28". The molecular absorption coeificient at 241 millimicrons is about 17,000.

A mixture of 40 parts of this compound with 98 parts of acetic anhydride is heated at C. for 6 hours, and further treated as in the reaction sequence in the preceding example, to yield 6ot-n1ethyl-1G-dehydroprogesterone in essentially the same yield. As a variation, 1,2-dichloroethane can be used in lieu of dichloromethane.

Example 5 let maximum is observed at 241 millimicrons with a molecular extinction of about 25,000.

Example 6 A solution of 10 parts of 6a-methyl-4,lG-pregnadien- 20-one in 360 parts of pure methanol is cooled to 8 C., and at that temperature treated by slow addition with 21.5 parts of a 35% aqueous hydrogen peroxide solution and 3.85 parts of a normal aqueous sodium hydroxide solution with continuous agitation. The reaction mixture is then maintained for 9 hours at about 2 C. after which 0.26 part of glacial acetic acid is added. The neutralized methanolic solution is filtered, and the filtrate is diluted with water to precipitate the 6ot-methy1-16a,17a-epoxyprogesterone.

To 5 parts of this epoxide in 10 parts of glacial acetic acid is added a saturated solution of hydrogen bromide in 7 parts of glacial acetic acid, and the mixture is permitted to stand at room temperature for 30 minutes. The mixture is then poured into ice water, and the bromohydrin is extracted with ether. Upon evaporation of the ether, the dry bromohydrin is refluxed for 2 hours in methanolic solution with twice its weight of Raney nickel. The Raney nickel is removed by filtration, and the methanolic solution is evaporated almost to dryness. On recrystallization from aqueous. acetone, the 6a-methyl-l7a-hydroxy-4- p1egnene-3,20-dione thus obtained melts at about 211- 213 C. Acylation by conventional procedure of such 6a-alkyl-l7a-hydroxy-4-pregnene-3,20-diones yields highly potent progestational agents.

Example 7 A mixture of 40 parts of 22--iso-4-spirosten-3-one and 98 parts of acetic anhydride is heated at 195 C. for 6 hours, and thereafter worked up as in Example 3 to afiord a high yield of 4,16-pregnadiene-3,20-dione, melting, at about 186-189 C.

What is claimed is:

1. In the preparation of a member of the class consisting of l66-(6-acetoxy-y-methylpentanoyloxy)-4-pregnene-3,20-dione and its lower 6a-alkyl derivatives wherein the lower alkyl group contains less than 3 carbon atoms,

, the step of heating the corresponding member of the class consisting of 3,26-diacetoxy-3,5,20(22)-furostatriene and its lower 6-alkyl derivatives with strong alkali in a lower alkanol,followed by contacting the resulting member of the class consisting of 26-hydroxy-4,20(22)-furostadien- 3-one and its 6- lower alkyl derivatives with acetic anhydride, and contacting the resulting 26-acetate with chromium trioxide.

2.-In the preparation of Goa-methyl-l6fi-(5-acetoxy-y- 10 methylpentanoyloxy)-4-pregnene-3,20-dione, the step of heating 6-methyl-3,26-diacetoxy-3,5,20(22)-furostatriene with strong alkali in a lower alkanol, followed by con- 5 nnhydride is used in pyridine solution. 7 I

4. Sa -hydroXy 6B-n1ethyl-22-isospirostau-3-one.'

References Cited in the file of this patent UNITED STATES PATENTS Marker July 4, 1944 Rosenkranz et al 'Apr 20, 1954 

1. IN THE PREPARATION OF MEMBER OF THE CLASS CON SISTING OF 16B-($-ACETOXY-Y-METHYLPENTANOYLOXY)-4-PREGNENE-3,20-DIONE AND ITS LOWER 6A-ALKYL DERIVATIVES WHEREIN THE LOWER ALKYL GROUP CONTAINS LESS THAN 3 CARBON ATOMS, THE STEP OF HEATING THE CORRESPONDING MEMBER OF THE CLASS CONSISTING OF 3,26-DIACETOXY-3,5,20(22)-FUROSTATRIENE AND ITS LOWER 6-ALKYL DERIVATIVES WITH STRONG ALKALI IN A LOWER ALKANOL, FOLLOWED BY CONTACTING THE RESURTING MEMBER OF THE CLASS CONSISTING OF 26-HYDROXY-4,20(22)-FUROSTADIEN3-ONE AND ITS 6-LOWER ALKYL DERIVATIVES WITH ACETIC ANHYDRIDE, AND CONTACTING THE RESULTING 26-ACETATE WITH CHROMIUM TRIOXIDE.
 4. 5A-HYDROXY-6B-METHYL-22-ISOSPIROSTAN-3-ONE. 